Succinate is a paracrine signal for liver damage

BACKGROUND/AIMS: A G-protein-coupled succinate receptor has recently been identified in several tissues, including the liver. The objectives of this work were to determine the hepatic cell types that express this receptor and to determine its physiological role. METHODS: Expression and distribution of the succinate receptor was determined by RT-PCR and confocal immunofluorescence. Biochemical assays were used to measure succinate and cAMP. Cytosolic Ca2+ was monitored in single cells by time-lapse imaging. Western blot was used to study the effect of succinate on activation of hepatic stellate cells. RESULTS: The succinate receptor was expressed in quiescent hepatic stellate cells, and expression decreased with activation. Ischemia induced release of succinate in isolated perfused livers. In contrast to what is observed in cell expression systems, succinate did not inhibit cAMP production or increase cytosolic Ca2+ in primary hepatic stellate cells. However, succinate accelerated stellate cell activation. CONCLUSIONS: Hepatic stellate cells express the succinate receptor. Succinate may behave as a paracrine signal by which ischemic hepatocytes trigger stellate cell activation.